title: Embryonic liver fodrin involved in hepatic stellate cell activation and formation of regenerative nodule in liver cirrhosis.
abstract: Transforming growth factor (TGF) β(1) plays a critical role in liver fibrosis. Previous studies demonstrated embryonic liver fodrin (ELF), a β-spectrin was involved in TGF-β/Smad signalling pathway as Smad3/4 adaptor. Here we investigate the role of ELF in pathogenesis of liver cirrhosis. In carbon tetrachloride (CCl(4))-induced mice model of liver cirrhosis, ELF is up-regulated in activated hepatic stellate cells (HSCs), and down-regulated in regenerative hepatocytes of cirrhotic nodules. In activated HSCs in vitro, reduction of ELF expression mediated by siRNA leads to the inhibition of HSC activation and procollagen I expression. BrdU assay demonstrates that down-regulation of ELF expression does not inhibit proliferation of activated HSCs in vitro. Immunostaining of cytokeratin 19 and Ki67 indicates that regenerative hepatocytes in cirrhotic liver are derived from hepatic progenitor cells (HPC). Further study reveals that HPC expansion occurs as an initial phase, before the reduction of ELF expression in regenerative hepatocytes. Regenerative hepatocytes in cirrhotic liver show the change in proliferative activity and expression pattern of proteins involved in G1/S transition, which suggests the deregulation of cell cycle in regenerative hepatocytes. Finally, we find that ELF participates in TGF-β/Smad signal in activated HSCs and hepatocytes through regulating the localization of Smad3/4. These data reveal that ELF is involved in HSC activation and the formation of regenerative nodules derived from HPC in cirrhotic liver.
authors.affiliation: Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Tu
authors.forename: Ying
authors.initials: Y
authors.lastname: Chang
authors.forename: Jinjian
authors.initials: J
authors.lastname: Yao
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Xiang
authors.initials: X
authors.lastname: Jiang
authors.forename: Xingxing
authors.initials: X
authors.lastname: He
authors.forename: Jusheng
authors.initials: J
authors.lastname: Lin
authors.forename: Yuhu
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000502:physiology*; D008099:Liver / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D013049:Spectrin / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D002251:Carbon Tetrachloride; D002352:Carrier Proteins; D008840:Microfilament Proteins; D051900:Smad3 Protein; D051901:Smad4 Protein; D013049:Spectrin; C497791:Smad3 protein, mouse; C490810:Smad4 protein, mouse